Work

Derlin Rhomboid Pseudoproteases Employ Substrate Engagement and Lipid Distortion Function for Retrotranslocation of ER Multi-Spanning Membrane Substrates

Year: 2021

Type: article

Abstract: Nearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane where they are correctly folded, assembled, and then delivered to their final cellular destinations. In order to prevent the accumulation of misfolded membrane proteins, ER associated degradation (ERAD) moves these clients from the ER membrane to the cytosol; a process known as retrotranslocation. Our recent work in S. cerevisiae has revealed a derlin rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study, we sought to understand the mechanism associated with Dfm1’s actions and found that Dfm1’s conserved rhomboid residues are critical for membrane protein retrotranslocation. Specifically, we identified several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 has retained the lipid thinning functions of its rhomboid protease predecessors to facilitate in the removal of ER membrane substrates. We find this substrate engagement and lipid thinning feature is conserved in its human homolog, Derlin-1. Utilizing interaction studies and molecular dynamics simulations, this work reveals that rhomboid pseudoprotease derlins employ novel mechanisms of substrate engagement and lipid thinning for catalyzing extraction of multi-spanning membrane substrates.

Source: Cell Reports

DOI: 10.1016/j.celrep.2021.109840